(i) Field of the Invention
The present invention relates to preparation of dehydrogenated lactam drugs including synthesis of dehydrogenated aripiprazole and cilostazol.
(ii) Background of the Invention
Many of the lactam containing drugs are metabolized to their dehydrogenated form and are often biologically active. For example, carbostyril derivatives can be metabolized to form dehydrogenated carbostyril derivatives. An example of such a drug is aripiprazole which is metabolized by Cytochrome P450 2D6 (CYP2D6) and CYP3A4 to give the active metabolite dehydro aripiprazole (7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4-dehydro-2-(1H) quinolinone). (Kirschbaum et al., The World Journal of Biological Chemistry, 2008 9(3), 212-8). Satyanarayana et al. recently reported a method for synthesizing dehydro aripiprazole using dichlorodicyanoquinone. (Hetercyclic Communications, 2005, 11(6), 485-490). However, the procedure reported results in moderate yield (42.5%). While dehydro aripiprazole is commercially available it is exorbitantly expensive. For example, it costs more than $13/mg from SynFine Research Inc. As such, a more efficient less expensive methodology is needed to produce dehydro aripiprazole and other oxidized lactam and carbostyril derivative drugs.